"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
DURAGESIC contains fentanyl, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. DURAGESIC can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing DURAGESIC in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence].
Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse and addiction since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Respiratory Depression and Death
Respiratory depression is the chief hazard of DURAGESIC. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.
DURAGESIC has a narrow indication and should be prescribed only by healthcare professionals who are knowledgeable in the administration of potent opioids and management of chronic pain [see INDICATIONS AND USAGE]. DURAGESIC is contraindicated for use in conditions in which the risk of life-threatening respiratory depression is significantly increased, including use as an as-needed analgesic, use in non-opioid tolerant patients, acute pain, and postoperative pain [see CONTRAINDICATIONS]. Proper dosing and titration of DURAGESIC are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the DURAGESIC dose when converting patients from another opioid medication, can result in fatal overdose with the first dose. However, respiratory depression has also been reported with use of DURAGESIC in patients who are opioid-tolerant, even when DURAGESIC has been used as recommended and not misused or abused.
The mean half-life of fentanyl when delivered by DURAGESIC is approximately 20-27 hours. Serum fentanyl concentrations continue to rise for the first two system applications. In addition, significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed [see CLINICAL PHARMACOLOGY].
Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening or fatal respiratory depression can occur at any time during the use of DURAGESIC, the potential for serious, life threatening, or fatal respiratory depression is greatest during the first two applications following initiation of dosing, or following an increase in dosage. Closely monitor patients for respiratory depression when initiating therapy with DURAGESIC, especially within the initial 24-72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. Because significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed, respiratory depression may persist beyond the removal of DURAGESIC. Monitor patients for respiratory depression after patch removal to ensure that the patient's respiration has stabilized for at least 24 to 72 hours or longer as clinical symptoms dictate.
Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE].
A considerable amount of active fentanyl remains in DURAGESIC even after use as directed. Death and other serious medical problems have occurred when children and adults were accidentally exposed to DURAGESIC. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death. Placing DURAGESIC in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death.
Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure to DURAGESIC (see DOSAGE AND ADMINISTRATION ).
Elderly, Cachectic, and Debilitated Patients
Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance. Therefore, monitor these patients closely, particularly when initiating therapy with DURAGESIC and when given in conjunction with other drugs that depress respiration [see Use In Specific Populations].
Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy with DURAGESIC, as in these patients, even usual therapeutic doses of DURAGESIC may decrease respiratory drive to the point of apnea [see WARNINGS AND PRECAUTIONS]. Consider the use of alternative non-opioid analgesics in these patients if possible.
Head Injuries and Increased Intracranial Pressure
Avoid use of DURAGESIC in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. In addition, opioids may obscure the clinical course of patients with head injury. Monitor patients with brain tumors who may be susceptible to the intracranial effects of CO2 retention for signs of sedation and respiratory depression, particularly when initiating therapy with DURAGESIC, as DURAGESIC may reduce respiratory drive and CO2 retention can further increase intracranial pressure.
Interactions with Other CNS Depressants, Alcohol, and Drugs of Abuse
The concomitant use of DURAGESIC with other central nervous system depressants, including, but not limited to, other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or coma. Monitor patients prescribed concomitant CNS active drugs for signs of sedation and respiratory depression, particularly when initiating therapy with DURAGESIC, and reduce the dose of one or both agents.
Interactions with CYP3A4 Inhibitors
The concomitant use of DURAGESIC with a CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving DURAGESIC and any CYP3A4 inhibitor for signs of sedation and respiratory depression for an extended period of time, and make dosage adjustments if warranted [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Application of External Heat
Exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as a result of exposure to heat. A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the DURAGESIC system increased fentanyl exposure [see CLINICAL PHARMACOLOGY].
Warn patients to avoid exposing the DURAGESIC application site and surrounding area to direct external heat sources [see DOSAGE AND ADMINISTRATION].
Patients with Fever
Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Monitor patients wearing DURAGESIC systems who develop fever closely for opioid side effects and reduce the DURAGESIC dose if necessary. Warn patients to avoid strenuous exertion that leads to increased core body temperature while wearing DURAGESIC to avoid the risk of potential overdose and death.
DURAGESIC may produce bradycardia. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with DURAGESIC.
A clinical pharmacology study with DURAGESIC in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because of the long half-life of fentanyl when administered as DURAGESIC and hepatic metabolism of fentanyl, avoid use of DURAGESIC in patients with severe hepatic impairment. Insufficient information exists to make precise dosing recommendations regarding the use of DURAGESIC in patients with impaired hepatic function. Therefore, to avoid starting patients with mild to moderate hepatic impairment on too high of a dose, start with one half of the usual dosage of DURAGESIC. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase. [see DOSING AND ADMINISTRATION, Use In Specific Populations and CLINICAL PHARMACOLOGY].
A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because of the long half-life of fentanyl when administered as DURAGESIC, avoid the use of DURAGESIC in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of DURAGESIC in patients with impaired renal function. Therefore, to avoid starting patients with mild to moderate renal impairment on too high of a dose, start with one half of the usual dosage of DURAGESIC. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see DOSING AND ADMINISTRATION, Use In Specific Populations and CLINICAL PHARMACOLOGY].
Use in Pancreatic/Biliary Tract Disease
DURAGESIC may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis for worsened symptoms. DURAGESIC may cause increases in the serum amylase concentration.
Avoidance of Withdrawal
Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion to another opioid or when decreasing or discontinuing DURAGESIC. Gradual reduction of the dose of DURAGESIC is recommended [see DOSAGE AND ADMINISTRATION and Drug Abuse and Dependence].
Driving and Operating Machinery
Strong opioid analgesics impair the mental or physical abilities required for the performance of potentially dangerous tasks, such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of the DURAGESIC.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide and Instructions for Use)
Provide patients receiving DURAGESIC patches the following information:
- DURAGESIC patches contain fentanyl, an opioid pain medicine that can cause serious breathing problems and death, especially if used in the wrong way and therefore should be taken only as directed. Instruct patients to call their doctor immediately or seek emergency medical help if they experience breathing problems while taking DURAGESIC.
- DURAGESIC contains fentanyl which has a high potential for abuse. Instruct patients, family members, and caregivers to protect DURAGESIC from theft or misuse in the work or home environment.
- Instruct patients to never give DURAGESIC to anyone other than the individual for whom it was prescribed because of the risk of death or other serious medical problems to that person for whom it was not intended.
- Advise patients never to change the dose of DURAGESIC or the number of patches applied to the skin unless instructed to do so by the prescribing healthcare professional.
- Warn patients of the potential for temperature-dependent
increases in fentanyl release from the patch that could result in an overdose
of fentanyl. Instruct patients to contact their healthcare provider if they
develop a high fever. Instruct patients to:
- avoid strenuous exertion that can increase body temperature while wearing the patch
- avoid exposing the DURAGESIC application site and surrounding area to direct external heat sources including heating pads, electric blankets, sunbathing, heat or tanning lamps, saunas, hot tubs or hot baths, and heated water beds.
- Keep DURAGESIC in a secure place out of the reach of children due to the high risk of fatal respiratory depression. DURAGESIC can be accidentally transferred to children. Instruct patients to take special precautions to avoid accidental contact when holding or caring for children.
- If the patch dislodges and accidentally sticks to the skin of another person, to immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual as accidental exposure may lead to death or other serious medical problems.
- To properly disposal of used and unneeded, unused DURAGESIC, remove them from their pouches, fold them so that the adhesive side of the patch adheres to itself, and flush them down the toilet.
- DURAGESIC may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Instruct patients to refrain from any potentially dangerous activity when starting on DURAGESIC or when their dose is being adjusted, until it is established that they have not been adversely affected.
- Advise women of childbearing potential who become, or are planning to become pregnant, to consult a healthcare provider prior to initiating or continuing therapy with DURAGESIC.
- Instruct patients not to use alcohol or other CNS depressants (e.g. sleep medications, tranquilizers) while using DURAGESIC because dangerous additive effects may occur, resulting in serious injury or death.
- Advise patients of the potential for severe constipation.
- When no longer needed, DURAGESIC should not be stopped abruptly to avoid the risk of precipitating withdrawal symptoms.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 μg/kg/day in males or 100 μg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC0-24h comparison).
There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays.
Impairment of Fertility
The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.
Use In Specific Populations
Pregnancy C: There are no adequate and well-controlled studies in pregnant women. DURAGESIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 μg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.
Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis).
Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis.
Labor and Delivery
Fentanyl readily passes across the placenta to the fetus; therefore, DURAGESIC is not recommended for analgesia during labor and delivery.
Fentanyl is excreted in human milk; therefore, DURAGESIC is not recommended for use in nursing women because of the possibility of effects in their infants.
The safety of DURAGESIC was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of DURAGESIC therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials.
The safety and effectiveness of DURAGESIC in children under 2 years of age have not been established.
To guard against excessive exposure to DURAGESIC by young children, advise caregivers to strictly adhere to recommended DURAGESIC application and disposal instructions [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Clinical studies of DURAGESIC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the DURAGESIC patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours [see CLINICAL PHARMACOLOGY].
Monitor geriatric patients closely for signs of sedation and respiratory depression, particularly when initiating therapy with DURAGESIC and when given in conjunction with other drugs that depress respiration [see WARNINGS AND PRECAUTIONS].
The effect of hepatic impairment on the pharmacokinetics of DURAGESIC has not been fully evaluated. A clinical pharmacology study with DURAGESIC in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of DURAGESIC, hepatic impairment would be expected to have significant effects on the pharmacokinetics of DURAGESIC. Avoid use of DURAGESIC in patients with severe hepatic impairment [see DOSING AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
The effect of renal impairment on the pharmacokinetics of DURAGESIC has not been fully evaluated. A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because there is in-vivo evidence of renal contribution to the elimination of DURAGESIC, renal impairment would be expected to have significant effects on the pharmacokinetics of DURAGESIC. Avoid the use of DURAGESIC in patients with severe renal impairment [see DOSING AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Neonatal Opioid Withdrawal Syndrome
Chronic maternal use of fentanyl can affect the neonate with subsequent withdrawal signs. Neonatal withdrawal syndrome presents as irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the dosage of last maternal use, and rate of elimination of the drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.
Last reviewed on RxList: 7/19/2012
This monograph has been modified to include the generic and brand name in many instances.
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